Process for preparing 16beta-methylprednisone



3,075,!Pfil Patented Jan. 29, 1963 This invention relates to an improved process for preparing iofi-methylprednisone acetate or l6fl-methylpregna- 1,4-diene-l7o:,2l-diol-3,l1,20-trione Zl-acetate.

16,8-methylprednisone is a known steroid, the pharmacological activity of which is described in Annals of New York Academy of Sciences, 82, 829 (1959).

The first processes for the preparation of trip-methylprednisone were described in J. Am. Chem. Society, 80, 4428 and 4435 (1958), and 82, 4012 (1960). These processes, however, are based on chemical reactions start ing from expensive raw materials and operating with low yields. The high cost of the final product thus obtained has till now limited its practical therapeutical use.

Particularly, 5,8-pregn-16-en-3e-ol-l1,20-dione-3 acetate has been described as a starting compound. It was prepared starting from 5fi-pregnane-3a,l7a,2l-triol-l1,20 dione-3,2l-diacetate, a steroid which already contains the 17a-hydroxy and 2l-acetoxy groups. These groups however must be first removed to prepare 5B-pregn-16-en-3aol-l1,20-dione3a-acetate, in which the same groups must be subsequently reintroduced to build up the structure of ISB-methylprednisone.

55-pregnane-3ot,17,21-triol-l l,20-dione-3,2l diacetate is obtained in turn from bile acids, the side chain of which can be degradated only through several expensive steps and with low yields.

A much more convenient synthetic route to ldti-methyh prednisone has been described by us in Experientia, 17, 448 (196i), and forms the subject of our copending application Serial No. 169,111, filed January 26, 1962. By this procedure, l6-methyl-5ot-pregnl6-en-3,B-ol-l1,20-dia mixture of lithium bromide and lithium carbonate in dimethylformamide.

The final product, i.e. lfi-methylprednisone-Zl-acetate, can be hydrolysed in known manner to obtain ldfi-methylprednisone.

It has been now found that one of the intermediate compounds of this process, i.e. loe-methylda-pregnaned7a, 21-diol-3,11,20-trione ZI-a'cetate can be converted into ISB-methylprednisone ZI-acetate by a still more convenient procedure, which is briefly described hereinafter and which forms the subject of the present application.

According to this invention, to 16,8-methyl-5 a-pregnano l7tx,2l-diol-3,l1,20-trione ZI-acetate (I) dissolved in an inert anhydrous organic solvent, a solution of one molecular equivalent of bromine dissolved in the same solvent is added at a temperature not exceeding C. By pouring the mass into ice water preferably buffered with sodium acetate, Z-bromo-l6fi-methyl-5a-pregnane-17a,2l-diol 3, 11,20-trione 2l-acetate (II) precipitates and is collected.

20 The compound II is refluxed with about 2 molecular equivalents of both lithium bromide and lithium carbonate in dimethylformamide in the absence of air and then the mass is poured into ice water previously made strongly acidic by the addition of hydrochloric acid. The precip- 5 itated product is 1fi-methyl-pregnd-ene-l7u,21-diol-3,11,

20-trione 2l-acetate (III).

The mono-one III is finally refluxed with selenium dioxide in a 1:10 mixture of acetic acid and, an inert organic solvent at a temperature between about 80 and 90 C.

0 Although many organic solvents proved satisfactory to this purpose, such as dioxane and many lower aliphatic a1 cohols, we prefer to employ tertiary butanol, which always gave excellent results. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate and the solution washed with sodium bicarbonate solution to neutral reaction, then with an ammonium sulfide and a sodium chloride solution in water and evaporated to dryness. The residue is recrystallized from aqueous acetone giving 16,8- methylprednisone Ill-acetate in a highly pure state.

The reaction scheme is as follows:

one Tie-acetate is advantageously used as the starting prod- A not. It can be easily obtained in good yields from steroids OHZOAC OHZO of plant origin as described, for instance, in Farmaco, 16, 0

58 (1961). on ---on The process consists in converting said l6-rnethyl-5ot- 0 OH; 0- CH epoxide by treatment with hydrogen peroxide in an alcoholic aqueous alkaline solution at room temperature for BMW 15-20 hours; the resulting epoxide is heated with p-toluene-sulphonic acid in an inert solvent, for example, ben- 0= L'ioos zone, at the boiling temperature of the solvent for 2-3 2 hours to obtain 16-methylene-5a-pregnane-3fl,l7a-diol-l1, I H

20 OHzOAc (IJHZOAC This last compound is converted, by mild reduction 0 CO with hydrogen, using palladium adsorbed on an earth alkali metal carbonate as a catalyst, in an inert organic solvent, to l6t3-methyl-5a-pregnane-3fi,17u-diol-l1,20-diacetone. 6 By oxidation of the thereby obtained 16/3-methyl-5an- 0H Ton, 07 Tong pregnane-3,s, 7a,2l-triol-il,20dione 21-acetate with a o= l one, which is practically free from Ida-isomer. l I

The 1fi-nrethyl-5a-pregnane-3B,17e-diol-11,20-dione is S602 converted into 165-methyl-5a-pregnane-3B,17ot,21-triol-11, I

III

sulphuric acid solution of chromic acid in acetone 16/8- 20-dione 21-acetate by treatment with bromine in an inert organic solvent at room temperature, evaporation of the solvent to dryness and refluxing the crude 2l-bromo-derivative for 15-18 hours with potassium acetate in aqueous methyl-5a-pregnane-17c,21-diol-3,1 1,20-trione-21 acetate stdered as a valuable advance, due to the nature of the end is obtained. This latter, through the 2,4-dibromo deproduct, i.e. of a steroid of high commercial value and rivative obtained by treatment with bromine in acetic high cost.

acid, gives the final product by dehydrobromination with The following example is illustrative of the invention.

3 Example To a solution of 40 g. of 16fi-methyl-5u-pregnane-17cc, 2'1-diol-3,l1,20-trione 2l-acetate in 900 ml. of dioxane a solution of 15.6 g. of bromine in 156 ml. of dioxane is quickly added, taking care that the temperature does not exceed 20 C. The mixture is then poured into litres of water containing 2 kg. of ice and g. of sodium acetate. The precipitate is collected and dried. Yield 45.2 g. (95 %)v of 2-brorno-l613-methyl-5u-pregnane-Um, 2l-diol-3,11,20-trione ZI-acetate, Ml. 135-l39 C., [u] +119 (-dioxane) or +111.6 (chloroform).

A mixture of 34.6 g. of the above bromo derivative, 370 ml. of dimethylformamid'e, 13.28 g. of lithium carbonate and 13.28 g. of lithium bromide is refluxed under a nitrogen atmosphere for about 1.5 hours. About 200 ml. of dimethylformamide are then removed by distillation and the residue is poured into 10 litres of water containing 2 kg. of ice and 80 ml. of cone. hydrochloric acid. The precipitate is collected and thoroughly washed with water. Yield 27.6 g. (95%) of l6;8-methylpregn-l-ene- 17a,2l-diol-3,11,2il-trione 21-acetate, MP. 225-230" C., [eth l-167 (c. 0.5, dioxane).

A mixture of 39 g. of the abovemono-ene, 1950 ml. of ter-butanol, 19.5 mi. of acetic acid and 11.7 g. of selenium dioxide is refluxed for about 10 hours under a nitrogen atmosphere, then a further quantity of 11.7 g. of selenium dioxide is added and refluxing is continued for about 20 hours. After cooling the mixture is filtered and evaporated to dryness. The residue is taken up with 2 litres of ethyl acetate and washed with an aqueous solution of sodium bicarbonate then with a water solution of ammonium sulfide and finally with a saturated water solution of sodium chloride. The ethyl acetate layer is evaporated to dryness and the residue is dissolved in hot acetone. After addition of water and cooling 16,8-rnethylprednisone 21-acetate precipitates and is collected and dried. Yield. 29.5 g. (76%), MP. 218-220 C., [M A-207.1 (c. 0.5, (II-1G The overall yield starting from 16-methyl-5a-pregnane- 17a,21'-diol-3,11,20-trione 21-acetate is thus about 68%.

We claim:

1. A process for preparing 16fi-methylprednisone 21- acetate, which comprises bringing together l-methyl- 5ot-pregnane-17a,21-diol 21-acetate and bromine in a molecular ratio of about 1:1 at a temperature not exceeding 20 C. in an inert organic solvent, refluxing the obtained 2 bromo methyl 5m pregnane 17a,2l diol- 3,11,20-trione 21-acetate with about two molecular equivalents of lithium bromide and lithium carbonate in dimethylformarnide, and refluxing the obtained 16B-methyl' pregn-1-ene-17a,21-cliol 21-acctate with selenium dioxide in an about 1:10 mixture of acetic acid and an inert organic solvent miscible with acetic acid.

2. A process as in claim 1, wherein the inert organic solvent miscible with acetic acid is a lower aliphatic alcohol.

3. A process as in claim alcohol is ter-butanol.

4. In a process for preparing lofi-niethylprednisone Zl-acetate, the steps which comprise bringing together 16fi-methyl-5a-pregnane-17e,21-diol 2l-acetate and bromine in a molecular ratio of about 1:1 at a temperature not exceeding 20 C. in dioxane, refluxing the obtained 2 bromo 16;? methyl 50c pregnane 17oc,21 diol- 3,11,20-trione 21-acetate with about two molecular equivalents of lithium bromide and lithium carbonate in dimethylformamide, and refluxing the obtained 16B-methylpregn-l-ene-l7u,21-diol 21-acetate with selenium dioxide in an about 1:10 mixture of acetic acid and ter-butauol.

2, wherein the lower aliphatic References (lited in the tile of this patent UNITED STATES PATENTS Counsell Nov. 7, 1961 Klimstra Jan. 23, 1962 Szpiliogel' et 480, May 1956.

UNITED STATES PATENT OFFICE CERTIFICATE OF C0RRECTI0N Patent No. 3,076,001 v January 29,, 1963 Giangiacomo Nathansohn et a1,

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 4 lines 5, 12 22 and 29 after "-l70I,21-di0l",, each occurrence insert 3 l1,20tri0ne Signed and sealed this 19th day of November 1963,

(SEAL) Attest:

EDWIN L, REYNOLDS ERNEST W. SWIDER t Attesting Officer AC ti ng Commissioner of Patents 

1. A PROCESS FOR PREPARING 16B-METHYLPREDNISONE 21ACETATE WHICH COMPRISES BRINGING TOGETHER 16B-METHYL5A-PREGNANE-17A,21-DIOL 21-ACETATE AND BROMINE IN A MOLECULAR RATIO OF ABOUT 1:1 AT A TEMPERATURE NOT EXCEEDING 20*C. IN AN INERT ORGANIC SOLVENT, REFLUXING THE OBTAINED 2 - BROMO - 16B METHYL- 5A - PREGNANE - 17A21, - DIOL3,11,20-TRIONE 21-ACETATE WITH ABOUT TWO MOLECULAR EQUIVALENTS OF LITHIUM BROMIDE AND LITHIUM CARBONATE IN DIMETHYLFORMAMIDE, AND REFLUXING THE OBTAINED 16B-METHYLPREGN-1-ENE-17A,21-DIOL 21-ACETATE WITH SELENIUM DIOXIDE IN AN ABOUT 1:10 MIXTURE OF ACETIC ACID AND AN INERT ORGANIC SOLVENT MISCIBLE WITH ACETIC ACID. 